title: Discovery of a human liver glycogen phosphorylase inhibitor that lowers blood glucose in vivo.
abstract: An inhibitor of human liver glycogen phosphorylase a (HLGPa) has been identified and characterized in vitro and in vivo. This substance, [R-(R*, S*)]-5-chloro-N-[3-(dimethylamino)-2-hydroxy-3-oxo-1-(phenylmethyl)pr opyl]-1H-indole-2-carboxamide (CP-91149), inhibited HLGPa with an IC50 of 0.13 microM in the presence of 7.5 mM glucose. CP-91149 resembles caffeine, a known allosteric phosphorylase inhibitor, in that it is 5- to 10-fold less potent in the absence of glucose. Further analysis, however, suggests that CP-91149 and caffeine are kinetically distinct. Functionally, CP-91149 inhibited glucagon-stimulated glycogenolysis in isolated rat hepatocytes (P < 0.05 at 10-100 microM) and in primary human hepatocytes (2.1 microM IC50). In vivo, oral administration of CP-91149 to diabetic ob/ob mice at 25-50 mg/kg resulted in rapid (3 h) glucose lowering by 100-120 mg/dl (P < 0.001) without producing hypoglycemia. Further, CP-91149 treatment did not lower glucose levels in normoglycemic, nondiabetic mice. In ob/ob mice pretreated with 14C-glucose to label liver glycogen, CP-91149 administration reduced 14C-glycogen breakdown, confirming that glucose lowering resulted from inhibition of glycogenolysis in vivo. These findings support the use of CP-91149 in investigating glycogenolytic versus gluconeogenic flux in hepatic glucose production, and they demonstrate that glycogenolysis inhibitors may be useful in the treatment of type 2 diabetes.
authors.affiliation: Department of Exploratory Medicinal Biology, Central Research Division, Pfizer, Inc, Groton, CT 06340, USA.
authors.forename: W H
authors.initials: WH
authors.lastname: Martin
authors.forename: D J
authors.initials: DJ
authors.lastname: Hoover
authors.forename: S J
authors.initials: SJ
authors.lastname: Armento
authors.forename: I A
authors.initials: IA
authors.lastname: Stock
authors.forename: R K
authors.initials: RK
authors.lastname: McPherson
authors.forename: D E
authors.initials: DE
authors.lastname: Danley
authors.forename: R W
authors.initials: RW
authors.lastname: Stevenson
authors.forename: E J
authors.initials: EJ
authors.lastname: Barrett
authors.forename: J L
authors.initials: JL
authors.lastname: Treadway
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002110:Caffeine / Q000494:pharmacology; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000201:enzymology; D008112:Liver Glycogen / Q000378:metabolism; D008297:Male; D051379:Mice; D008820:Mice, Obese; D006005:Phosphorylases / Q000037:antagonists & inhibitors*; D051381:Rats; D011994:Recombinant Proteins
chemical_list: D000577:Amides; D001786:Blood Glucose; C110844:CP 91149; D004791:Enzyme Inhibitors; D007211:Indoles; D008112:Liver Glycogen; D011994:Recombinant Proteins; D002110:Caffeine; D006005:Phosphorylases